A growing body of evidence supports a prominent role for inflammation in the development of atherosclerosis. The evolution of atheromatous lesions is guided in part by the action of inflammatory mediators, and in apparently healthy subjects, the presence of systemic inflammatory markers is positively correlated with the subsequent occurrence of cardiovascular disease. Nonetheless, the contributions of systemic inflammation to development of atherosclerosis are not well understood. The major component of systemic inflammation, the acute phase response (APR), is triggered in two phases. The first phase leads to the production of proinflammatory cytokines such as IL-lbeta, tumor necrosis factor alpha (TNFalpha) and IL-6 at the site of injury. The second phase involves the action of those cytokines on target organs such as the liver, where synthesis of acute phase proteins is stimulated or suppressed. IL-6, an indicator of increased risk for future myocardial infarction, exerts its effects on APR genes principally through the transcription factor Stat3. Stat3 is expressed as two isoforms with distinct biochemical properties. The use of an alternative splice acceptor site specifies the Stat3beta (Stat 3beta) isoform. We have used a novel approach to generate mice that are selectively unable to synthesize the Stat3beta isoform. Our preliminary observations uncover a role for Stat3beta in the modulation of Stat3-mediated transcription, and suggest that Stat3beta is essential for normal recovery from systemic inflammation. To explore the role of Stat3 isoforms in the regulation of the acute phase response, and the relation of the acute phase response to atherosclerosis, we will pursue three aims. We will develop detailed transcriptional maps of the hepatic and endothelial acute phase responses in normal and Stat3b-deficient mice by genome-wide microarray assays. Using a combination of biochemical and computational approaches, we will define how Stat3beta modulates expression of Stat3-responsive genes. Third, we will test the hypothesis that chronic systemic inflammation promotes development of atherosclerosis by examining the influence of Stat3beta-deficiency on development of atherosclerosis in mouse models.